Insulin- and Lipopolysaccharide-Mediated Signaling in Adipose Tissue Macrophages Regulates Postprandial Glycemia through Akt-mTOR Activation.

The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.

NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis.

Adipose tissue is central to regulation of energy homeostasis. Adaptive thermogenesis, which relies on mitochondrial oxidative phosphorylation (Ox-Phos), dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to type 2 diabetes and obesity. Here, we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves glucose homeostasis by upregulation of Ox-Phos and reciprocal downregulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance and limited weight gain. NFIA up-regulates Ox-Phos and brown-fat-specific genes by enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulates proinflammatory cytokine genes to ameliorate adipose tissue inflammation. NFIA binds to regulatory region of the Ccl2 gene, which encodes proinflammatory cytokine MCP-1 (monocyte chemoattractant protein-1), to down-regulate its transcription. CCL2 expression was negatively correlated with NFIA expression in human adipose tissue. These results reveal the beneficial effect of NFIA on glucose and body weight homeostasis and also highlight previously unappreciated role of NFIA in suppressing adipose tissue inflammation.

Definition, criteria, and core concepts of guidelines for the management of obesity disease in Japan.

To identify those who might benefit from weight reduction within a large population of obese individuals, Japan Society for the Study of Obesity (JASSO) advocated the concept of "obesity disease." Here we summarize the definition, criteria, and core concepts for the management of obesity disease based on JASSO's latest guideline. JASSO defines obesity as excessive fat storage in adipose tissue associated with a BMI of ≥25 kg/m2. The threshold BMI of obesity is low as compared to Western countries given that Japanese individuals tend to develop obesity-related health disorders at lower BMI. Obesity with a BMI of ≥35 kg/m2 is referred to as "high-degree obesity" as treatment strategies vary based on the degree of obesity. Obesity is diagnosed as "obesity disease" if accompanied by any of the 11 specific obesity-related health disorders that weight reduction can prevent or alleviate, or if it meets the criteria for visceral fat obesity with a visceral fat area of ≥100 cm2. The initial weight reduction goals for high-degree obesity disease range from 5% to 10% of their current body weight, depending on the associated health disorders. That for those with obesity disease who do not qualify as high-degree is 3% or more. If these initial goals are not achieved, intensifying dietary therapy or introducing drug therapy (or both) may be necessary. While surgical treatment is primarily indicated for high-degree obesity disease, it might be appropriate for cases of obesity disease with a BMI <35 kg/m2, depending on the accompanying health disorders. Enhancing the quality of life for individuals with obesity or obesity disease necessitates a broader societal approach, emphasizing the resolution of related stigma.

Genome-wide association studies identify two novel loci conferring susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes.

Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P < 1.0 × 10-4) in an independent case-control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stages 1 and 2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, P = 1.62 × 10-9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11-1.23, and rs140508424 within PALM2 on chromosome 9, P = 4.19 × 10-8, OR = 1.61, 95% CI 1.36-1.91. However, the association of these two loci was not replicated in Korean, European or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (P = 2.17 × 10-6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.

StepAdd: A personalized mHealth intervention based on social cognitive theory to increase physical activity among type 2 diabetes patients.

OBJECTIVE: Investigate the preliminary efficacy and feasibility of a personalized mobile health (mHealth) intervention based on social cognitive theory (SCT) to promote physical activity among type 2 diabetes patients via self-monitoring, goal setting, and automatic feedback. METHODS: We conducted a pilot study involving 33 type 2 diabetes patients attending Mitsui Memorial Hospital in Japan using a pre-post evaluation design over 12 weeks. Participants measured daily step count, body weight, and blood pressure at home, with the measurements synchronized with the StepAdd application (app) automatically. Participants used the app to review daily results, update personalized step goals, identify individualized barriers to achieving the step goals, find coping strategies to overcome each barrier, and implement these strategies, thereby building effective coping skills to meet the goals. Pharmacists examined the usage of the app and provided coaching on lifestyle modifications. Ultimately, patients established skills to enhance diabetes self-care by using the app. RESULTS: Daily step count increased dramatically with high statistical significance (p < 0.0001), from a mean of 5436 steps/day to 10,150 steps/day, an 86.7 % increase. HbA1c (p = 0.0001) and BMI (p = 0.0038) also improved. Diabetes self-care in diet, exercise, and foot care as well as self-management behavior, self-regulation, and self-efficacy in achieving daily step goals showed significant improvements. The retention rate of the study was very high, at 97.0 % (n = 32). CONCLUSIONS: A personalized smartphone-based mHealth intervention based on SCT is feasible and effective at promoting physical activity among type 2 diabetes patients. The methodology of the intervention could be readily applied to other patient populations.

Blood levels of nicotinic acid negatively correlate with hearing ability in healthy older men.

BACKGROUND: Age-related hearing loss (ARHL) is a common phenomenon observed during aging. On the other hand, the decrease in Nicotinamide adenine dinucleotide (NAD +) levels is reported to be closely related to the age-related declines in physiological functions such as ARHL in animal studies. Moreover, preclinical studies confirmed NAD + replenishment effectively prevents the onset of age-related diseases. However, there is a paucity of studies on the relationship between NAD+ metabolism and ARHL in humans. METHODS: This study was analyzed the baseline results of our previous clinical trial, in which nicotinamide mononucleotide or placebo was administered to 42 older men (Igarashi et al., NPJ Aging 8:5, 2022). The correlations between blood levels of NAD+-related metabolites at baseline and pure-tone hearing thresholds at different frequencies (125, 250, 500, 1000, 2000, 4000, and 8000 Hz) in 42 healthy Japanese men aged > 65 years were analyzed using Spearman's rank correlation. Multiple linear regression analysis was performed with hearing thresholds as the dependent variable and age and NAD+-related metabolite levels as independent variables. RESULTS: Positive associations were observed between levels of nicotinic acid (NA, a NAD+ precursor in the Preiss-Handler pathway) and right- or left-ear hearing thresholds at frequencies of 1000 Hz (right: r = 0.480, p = 0.001; left: r = 0.422, p = 0.003), 2000 Hz (right: r = 0.507, p < 0.001, left: r = 0.629, p < 0.001), and 4000 Hz (left: r = 0.366, p = 0.029). Age-adjusted multiple linear regression analysis revealed that NA was an independent predictor of elevated hearing thresholds (1000 Hz (right): p = 0.050, regression coefficient (ß) = 1610; 1000 Hz (left): p = 0.026, ß = 2179; 2000 Hz (right): p = 0.022, ß = 2317; 2000 Hz (left): p = 0.002, ß = 3257). Weak associations of nicotinic acid riboside (NAR) and nicotinamide (NAM) with hearing ability were observed. CONCLUSIONS: We identified negative correlations between blood concentrations of NA and hearing ability at 1000 and 2000 Hz. NAD+ metabolic pathway might be associated with ARHL onset or progression. Further studies are warranted. TRIAL REGISTRATION: The study was registered at UMIN-CTR (UMIN000036321) on 1st June 2019.

Comparison of bleeding complications after pediatric kidney biopsy between intravenous sedation and general anesthesia: a nationwide cohort study.

BACKGROUND: An increasing number of studies are evaluating the safety of intravenous sedation compared with that of general anesthesia; however, data on bleeding complications after pediatric percutaneous renal biopsy performed under intravenous sedation or general anesthesia are lacking. We aimed to examine differences in bleeding complications between intravenous sedation and general anesthesia in pediatric patients. METHODS: Data of pediatric patients aged ≤ 15 years undergoing percutaneous kidney biopsy for kidney disease between July 2007 and March 2019 were retrieved from a national inpatient database in Japan. We examined differences in bleeding complications after renal biopsy performed under intravenous sedation, defined by the absence of the record of general anesthesia with intubation but by the presence of intravenous sedation during biopsy, and general anesthesia, defined by the presence of the record of general anesthesia with intubation during biopsy, among pediatric patients admitted for percutaneous renal biopsy. We performed binomial regression using overlap weights based on propensity scores for patients receiving intravenous sedation. Analyses stratified by age or sex, a sensitivity analysis using generalized estimating equations considering cluster effects by hospital among a propensity score-matched cohort, and another sensitivity analysis using the instrumental variable method were performed to confirm the robustness of the results. RESULTS: We identified 6,560 biopsies performed in 5,999 children aged 1-15 years from 328 hospitals and 178 events. Only three severe complications and no death were observed. No significant difference in the proportion of bleeding complications was observed between procedures performed under intravenous sedation and those performed under general anesthesia (unadjusted proportions, 2.8% and 2.3%; adjusted proportions, 2.5% and 2.2%), with an unadjusted relative risk of 1.21 (95% confidence interval, 0.80-1.81) and adjusted relative risk of 1.13 (95% confidence interval, 0.74-1.73). Both age- and sex-stratified analyses yielded similar results. The analysis using generalized estimating equation and the instrumental variable method showed relative risks of 0.95 (95% confidence interval, 0.48-1.88) and 1.18 (95% confidence interval, 0.74-1.89), respectively. CONCLUSION: This retrospective cohort study using a national database revealed that the risk of biopsy-related bleeding was comparable between intravenous sedation and general anesthesia during pediatric percutaneous kidney biopsy, suggesting that intravenous sedation alone and general anesthesia may have a similar bleeding risk in pediatric percutaneous kidney biopsies.

NFIA differentially controls adipogenic and myogenic gene program through distinct pathways to ensure brown and beige adipocyte differentiation.

The transcription factor nuclear factor I-A (NFIA) is a regulator of brown adipocyte differentiation. Here we show that the C-terminal 17 amino acid residues of NFIA (which we call pro#3 domain) are required for the transcriptional activity of NFIA. Full-length NFIA-but not deletion mutant lacking pro#3 domain-rescued impaired expression of PPARγ, the master transcriptional regulator of adipogenesis and impaired adipocyte differentiation in NFIA-knockout cells. Mechanistically, the ability of NFIA to penetrate chromatin and bind to the crucial Pparg enhancer is mediated through pro#3 domain. However, the deletion mutant still binds to Myod1 enhancer to repress expression of MyoD, the master transcriptional regulator of myogenesis as well as proximally transcribed non-coding RNA called DRReRNA, via competition with KLF5 in terms of enhancer binding, leading to suppression of myogenic gene program. Therefore, the negative effect of NFIA on the myogenic gene program is, at least partly, independent of the positive effect on PPARγ expression and its downstream adipogenic gene program. These results uncover multiple ways of action of NFIA to ensure optimal regulation of brown and beige adipocyte differentiation.

Addressing screams for evidence on renoprotection by GLP-1 receptor agonists.

Although growing evidence supports the benefits of glucagon-like peptide-1 receptor agonists, the renoprotective effects were not fully proven in clinical trials. Now, Xu et al. show that glucagon-like peptide-1 receptor agonists reduce the renal outcome compared with dipeptidyl peptidase-4 inhibitors in a retrospective cohort study of the participants in the Stockholm Creatinine Measurements project undertaken in Stockholm, Sweden. Despite some limitations, the study shows renoprotection by glucagon-like peptide-1 receptor agonists and raises hope about upcoming evidence from prospective clinical trials.

Impact of Glucose Tolerance and Its Change on Incident Proteinuria: Analysis of a Nationwide Population-Based Dataset.

INTRODUCTION: Although diabetes mellitus (DM) increases the risk of proteinuria, the relationship between prediabetes and proteinuria remains not fully understood. Further, whether the change in glucose is associated with the risk for proteinuria is unknown. METHODS: This was a retrospective cohort study that included 1,849,074 participants (median age, 45 years; 59.3% men). No participants were taking glucose-lowering medications, and none had positive proteinuria at the initial health check-up. Each participant was categorized into three groups: normal (hemoglobin A1c [HbA1c] of <5.7%, n = 1,563,121), prediabetes (HbA1c of 5.7-6.4%, n = 253,490), and DM (HbA1c of ≥6.5%, n = 32,463) groups. We investigated the association between each HbA1c category and incident proteinuria using Cox proportional hazards models. We analyzed the association between the annual change in HbA1c and the risk for proteinuria. RESULTS: A total of 65,954 participants developed proteinuria during the observation period. Not only DM (hazard ratio [HR]: 2.15, 95% confidence interval [CI]: 2.07-2.24) but also prediabetes (HR: 1.14, 95% CI: 1.12-1.17) was associated with a greater risk for proteinuria. The relative risk reduction for proteinuria that was associated with prediabetes and DM was 12.3% and 53.5%, respectively. An annual increase in HbA1c was associated with a greater risk for proteinuria. This association was more pronounced in participants having prediabetes. CONCLUSION: Not only DM but also prediabetes increased the risk for proteinuria. The influence of change in HbA1c on incident proteinuria was pronounced in people with prediabetes. Optimizing glucose would provide more benefit to individuals having prediabetes for proteinuria prevention.

Change in Cardiovascular Health Metrics and Risk for Proteinuria Development: Analysis of a Nationwide Population-Based Database.

INTRODUCTION: Evidence is lacking regarding the association between cardiovascular health (CVH) metrics and the risk for proteinuria. METHODS: We performed this observational cohort study including 865,087 participants (median age, 46 years, 60.7% men) with negative proteinuria at the initial health check-up, who underwent repeated health check-ups within 4 years. Ideal CVH metrics included nonsmoking, body mass index <25 kg/m2, physical activity at goal, eating breakfast, blood pressure <120/80 mm Hg, fasting plasma glucose <100 mg/dL, and total cholesterol <200 mg/dL. The primary outcome was incident proteinuria, defined as ≥1 + on the urine dipstick test. RESULTS: Participants were categorized as having low CVH metrics defined as having 0-2 ideal CVH metrics (n = 84,439), middle CVH metrics defined as having 3-4 ideal CVH metrics (n = 335,773), and high CVH metrics defined as having 5-7 ideal CVH metrics (n = 444,875). Compared with low CVH metrics, middle CVH metrics (odds ratio (OR): 0.61, 95% CI: 0.59-0.63) and high CVH metrics (OR: 0.45, 95% CI: 0.43-0.46) were associated with a lower risk of proteinuria. The OR of a one-point increase in the ideal number of CVH metrics was 0.83 (95% CI: 0.82-0.83). All CVH metrics components except for ideal total cholesterol were associated with a decreased risk of proteinuria. A one-point improvement in the number of ideal CVH metrics at 1 year after the initial health check-up was associated with a decreased incidence of proteinuria (OR: 0.90, 95% CI: 0.89-0.92). CONCLUSION: Not only maintaining better CVH metrics but also improving CVH metrics would prevent developing proteinuria in a general population.

Evaluation of foot ulcer incidence in diabetic patients at a diabetic foot ulcer prevention clinic over a 10-year period.

The present study aimed to evaluate diabetes patients over a 10-year period that visited our outpatient clinic for prevention of diabetic foot ulcers and then investigate the incidence and aetiology of diabetic foot ulcers. The Department of Diabetes and Metabolic Diseases of a university hospital was in charge of the clinic that provided diabetes patients with individual education via the use of visualisation techniques. In this prospective cohort study, a total of 942 diabetes patients who visited the clinic were evaluated for neuropathy, angiopathy and medical history between November 2006 and March 2017. Using the patients' medical records, diabetic foot ulcer development was evaluated between the day of the first visit and December 31, 2018, with 20 out of 942 participants developing these ulcers. Over a period of 12, 60 and 120 months, the diabetic foot ulcer cumulative incidence was 0.2%, 2.4% and 5.8%, respectively. A history of diabetic foot ulcers and the male sex were shown by a Cox regression analysis to be correlated with diabetic foot ulcer development (Hazard Ratio [HR] 11.55, 95%CI 4.600-29.004, p < 0.001; and HR 3.55, 95%CI 1.031-12.196, p = 0.045, respectively). However, only five out of 20 participants with ulceration returned to the clinic for re-examination. In conclusion, a 12-month evaluation showed there was a low incidence of diabetic foot ulcers. These results might suggest that patients with a diabetic foot ulcer history need to undergo at least an annual follow-up in order to further reduce diabetic foot ulcer incidence, although studies involving control groups needs to be conducted, in presenting these as evidence.

Major complications after percutaneous biopsy of native or transplanted liver in pediatric patients: a nationwide inpatient database study in Japan.

AIM: Although major complication rates following percutaneous liver biopsy (PLB) have been reported to be higher in children than in adults, scarce data are available regarding pediatric patients stratified by native and transplanted liver. We aimed to assess the factors associated with major complications after percutaneous biopsy of native or transplanted liver using a nationwide inpatient database. METHODS: Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified pediatric patients who underwent PLB between 2010 and 2018. We described major complication rates and analyzed factors associated with major complications following PLB, stratified by native and transplanted liver. RESULTS: We identified 3584 pediatric PLBs among 1732 patients from 239 hospitals throughout Japan during the study period, including 1310 in the native liver and 2274 in the transplanted liver. Major complications following PLB were observed in 0.5% (n = 18) of the total cases; PLB in the transplanted liver had major complications less frequently than those in the native liver (0.2% vs. 1.0%, p = 0.002). The occurrence of major complications was associated with younger age, liver cancers, unscheduled admission, anemia or coagulation disorders in cases with native liver, while it was associated with younger age alone in cases with transplanted liver. CONCLUSIONS: The present study, using a nationwide database, found that major complications occurred more frequently in pediatric cases with native liver and identified several factors associated with its major complications.

Elucidating exercise-induced skeletal muscle signaling pathways and applying relevant findings to preemptive therapy for lifestyle-related diseases.

While it is well recognized that exercise represents a radical preventive and therapeutic measure for lifestyle-related diseases, it is clear that contemporary lifestyles abound with situations where exercise may be found difficult to implement on a continuous basis. Indeed, this has led to global expectations for elucidation of the exercise-activated skeletal muscle signaling pathways as well as for development of exercise mimics that effectively activate such pathways. It is shown that exercise activates the transcriptional coactivator PGC-1α via AMPK/SIRT1 in muscle, thereby not only enhancing mitochondrial function and muscle endurance but upregulating energy metabolism. Further, adipocyte-derived adiponectin is also shown to activate AMPK/SIRT1/PGC-1α via its receptor AdipoR1 in skeletal muscles. Thus, adiponectin/AdipoR1 signaling is thought to constitute exercise-mimicking signaling. Indeed, it has become clear that AMPK, SIRT1 and AdipoR activators act as exercise mimetics. With the crystal structures of AdipoR elucidated and humanized AdipoR mice generated toward optimization of candidate AdipoR-activators for human use, expectations are mounting for the clinical application in the near future of AdipoR activators as exercise mimetics in humans. This review provides an overview of molecules activated by exercise and compounds activating these molecules, with a focus on the therapeutic potential of AdipoR activators as exercise mimetics.

New classification and diagnostic criteria for insulin resistance syndrome.

This report of a working group established by the Japan Diabetes Society proposes a new classification and diagnostic criteria for insulin resistance syndrome. Insulin resistance syndrome is defined as a condition characterized by severe attenuation of insulin action due to functional impairment of the insulin receptor or its downstream signaling molecules. This syndrome is classified into two types: genetic insulin resistance syndrome, caused by gene abnormalities, and type B insulin resistance syndrome, caused by autoantibodies to the insulin receptor. Genetic insulin resistance syndrome includes type A insulin resistance as well as Donohue and Rabson-Mendenhall syndromes, all of which are caused by abnormalities of the insulin receptor gene; conditions such as SHORT syndrome caused by abnormalities of PIK3R1, which encodes a regulatory subunit of phosphatidylinositol 3-kinase; conditions caused by abnormalities of AKT2, TBC1D4, or PRKCE; and conditions in which a causative gene has not yet been identified. Type B insulin resistance syndrome is characterized by severe impairment of insulin action due to the presence of insulin receptor autoantibodies. Cases in which hypoglycemia alone is induced by autoantibodies that stimulate insulin receptor were not included in Type B insulin resistance syndrome.

Impact of body mass index on in-hospital mortality in older patients hospitalized for bacterial pneumonia with non-dialysis-dependent chronic kidney disease.

BACKGROUND: Low body mass index (BMI) in older individuals with decreased kidney function is important because of its association with poor prognosis and frailty. Herein, we aimed to clarify the association between BMI and in-hospital mortality among older patients with non-dialysis-dependent chronic kidney disease (CKD) stratified by kidney function. METHODS: Using data from the Medical Vision Database, this multicentre cohort study included people aged ≥ 60 years with an estimated glomerular filtration rate of < 60 ml/min/1.73 m2 but without dialysis dependency, hospitalised for bacterial pneumonia during 2014-2019. We compared the risk of in-hospital death between patients with BMI categories based on the quartiles (low, medium-low, medium-high, and high) setting medium-high BMI as a reference. We further assessed the association with BMI using a cubic spline, setting BMI as a nonlinear continuous variable and a BMI of 22 kg/m2 as a reference. We also evaluated the association between BMI and kidney function using a generalised additive model adjusted for interaction terms between nonlinear continuous BMI and kidney function. RESULTS: We obtained data for 3,952 patients, with 350 (8.9%) in-hospital deaths. When compared with medium-high BMI, low BMI was associated with an increased risk of death and longer hospital stay, whereas the other two categories were comparable. Models using a cubic spline showing an association between BMI and in-hospital death showed an L-shaped curve; BMI < 22.0 kg/m2 was associated with an increased risk for mortality, and at a BMI of 18.5 kg/m2, the odds ratio was 1.43 with a 95% confidence interval of 1.26-1.61 when compared with a BMI of 22.0 kg/m2. Analysis of the interactive effects of kidney function using the generalised additive model showed that a protective association of high BMI tapered along with decreased kidney function. CONCLUSIONS: This cohort study suggests not only that lower BMI and low kidney function are associated with in-hospital mortality independently but also that the protective effects of high BMI weaken as kidney function decreases via the analysis of the interaction terms. This study highlights the necessity for the prevention of underweight and demonstrates the interaction between BMI and kidney function in older patients with non-dialysis-dependent CKD.

Effect of Branched-Chain Amino Acid Infusion on In-Hospital Mortality of Patients With Hepatic Encephalopathy and End-Stage Kidney Disease: A Retrospective Cohort Study Using a National Inpatient Database.

OBJECTIVES: Renal failure and hepatic cirrhosis are mutually aggravating factors. However, no specific therapeutic strategies for hepatic encephalopathy (HE) and end-stage kidney disease have been established. The coexistence, with an extremely poor prognosis, makes randomized controlled trials unfeasible. We evaluated whether an infusion of branched-chain amino acids was associated with mortality in patients hospitalized for HE and end-stage kidney disease. DESIGN AND METHODS: Using the Japanese Diagnosis Procedure Combination database, we retrospectively identified patients with HE and end-stage kidney disease who received hemodialysis within 2 days of admission from July 2011 to March 2017. We divided the patients into those who received branched-chain amino acid infusion within 2 days of admission and those who did not. We conducted analyses using overlap weights based on propensity scores to compare in-hospital mortality between the groups. Sub-group analysis was conducted by stratifying patients by Child-Pugh class. RESULTS: We identified 553 eligible patients, including 503 patients who received branched-chain amino acid infusion and 50 who did not. The patients who received branched-chain amino acid infusion had lower mortality than those who did not (10.2% vs. 20.1%, relative risk 0.51, 95% confidence interval 0.27-0.95). Sub-group analysis showed that branched-chain amino acid infusion was associated with decreased in-hospital mortality in patients with Child-Pugh class C (16.2% vs. 39.0%, relative risk 0.41, 95% confidence interval 0.23-0.76). CONCLUSIONS: Branched-chain amino acid infusion may improve the prognosis of HE in patients with end-stage kidney disease, particularly those with lower liver function. Further research is necessary to provide a suitable treatment for HE in patients with end-stage kidney disease.

LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic rs641738 C>T variant in the lysophosphatidylinositol acyltransferase 1 (LPIAT1)/membrane bound O-acyltransferase domain-containing 7, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes. DESIGN: We generated the hepatocyte-specific Lpiat1 knockout mice to investigate the function of Lpiat1 in vivo. We also depleted LPIAT1 in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids. RESULTS: The hepatocyte-specific Lpiat1 knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of LPIAT1 in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride. CONCLUSION: We found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.